Browsing by Author "Saatçi, Ö."
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Open Access Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer(Nature Research, 2020) Saatçi, Ö.; Kaymak, A.; Raza, Umar; Ersan, Pelin G.; Akbulut, Özge; Banister, C. E.; Sikirzhytski, V.; Tokat, Ünal Metin; Aykut, Gamze; Ansari, Suhail A.; Tatlı-Doğan, H.; Doğan, M.; Jandaghi, P.; Işık, A.; Gündoğdu, F.; Kösemehmetoğlu, K.; Dizdar, Ö.; Aksoy, S.; Akyol, A.; Üner, A.; Buckhaults, P. J.; Riazalhosseini, Y.; Şahin, ÖzgürChemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.Item Open Access Thymidylate synthase maintains the de-differentiated state of triple negative breast cancers(Nature Publishing Group, 2019-02) Siddiqui, A.; Gollavilli, P. N.; Schwab, A.; Vazakidou, M. E.; Ersan, Pelin G.; Ramakrishnan, M.; Pluim, D.; Coggins, Si’A.; Saatçi, Ö.; Annaratone, L.; Schellens, J. HM; Kim, B.; Asangani, İ. A.; Rasheed, S. A. K.; Marchiò, C.; Şahin, Özgür; Ceppi, P.Cancer cells frequently boost nucleotide metabolism (NM) to support their increased proliferation, but the consequences of elevated NM on tumor de-differentiation are mostly unexplored. Here, we identified a role for thymidylate synthase (TS), a NM enzyme and established drug target, in cancer cell de-differentiation and investigated its clinical significance in breast cancer (BC). In vitro, TS knockdown increased the population of CD24+ differentiated cells, and attenuated migration and sphere-formation. RNA-seq profiling indicated repression of epithelial-to-mesenchymal transition (EMT) signature genes upon TS knockdown, and TS-deficient cells showed an increased ability to invade and metastasize in vivo, consistent with the occurrence of a partial EMT phenotype. Mechanistically, TS enzymatic activity was found essential for maintenance of the EMT/stem-like state by fueling a dihydropyrimidine dehydrogenase—dependent pyrimidine catabolism. In patient tissues, TS levels were found significantly higher in poorly differentiated and in triple negative BC, and strongly correlated with worse prognosis. The present study provides the rationale to study in-depth the role of NM at the crossroads of proliferation and differentiation, and depicts new avenues for the design of novel drug combinations for the treatment of BC.